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Region Hovedstaden - en del af Københavns Universitetshospital

PDE inhibitors: A new strategy in the treatment of schizophrenia?

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Recently, a number of studies on the effects of phosphodiesterase (PDE) inhibitors on cognition have beenpublished (for a review see (Reneerkens et al. 2009)). Especially the PDE4 (cAMP specific) inhibitor Rolipram and the PDE5 (cGMP specific) inhibitor Sildenafil (Viagra) have been thoroughly investigated for cognitive effects in animal models. It seems that Rolipram has beneficial effect on memory consolidation and spatial memory in animal models. Sildenafil has positive effects on memory performance, object recognition tasks, and memory consolidation in animal models. Furthermore Sildenafil has been tested in humans in three different studies. Grass et al. (2001) showed no important impairment of psychophysical performance in a (single) blinded crossover experiment except for a minor decrease in reaction time and an increase in
error frequency. ERP were recorded in a spatial auditory attention and a visual word recognition task. Schultheiss et al. (2001) showed that in a double blinded auditory selective attention study sildenafil enhanced; the ability to focus attention (amplitude enhancement of Nd-effect) and to select relevant target stimuli (P3 component). Goff et al. (2009) tested schizophrenia patients with varying doses of sildenafil but found no changes in psychiatric symptom ratings (BPRS) or a number of cognitive tasks. Siuciak (2006-8) has shown
that PDE10A knockout mice have deficits in the learning time of acquisition of conditioned avoidance responding (CAR), these results are consistent with Becker & Grecksch (2008) who found that papaverine, in doses that did no effect locomotor activity, suppressed CAR. A single paper has shown that the PDE10A-i TP-10 reversed amphetamine induced auditory sensory gating (intracranial P50 paradigm, effect parameters: P20, N40) deficits (Schmidt et al. 2008), although these results have not been found in PPI paradigms
(Weber et al. 2009;Schmidt et al. 2008). Further evidence of PDE10A-i’s antipsychotic-like profile was found in a paradigm of attentional set-shifting in rats designed to reflect frontal function in man, where papaverine
attenuated the PCP-induced deficits (Rodefer et al. 2005). Likewise findings from Morris water maze (Hebb et al. 2008a;Siuciak et al. 2006b) indicates that reduce PDE10A activity leads to reduced spatial memory. All of the above suggest that PDE10A-iinhibitors may hold promises as an antipsychotic agent, with the same cognitive profile as ordinary antipsychotics. Therefore, in this double-blind, placebo controlled cross-over study (PhD project) it will be investigated whether the phosphodiesterase (PDE) inhibitor papaverine has the
capacity to reduce cognitive deficits associated with schizophrenia. Twenty chronic but treatment-stable schizophrenia patients and 20 age and gender matched healthy controls will be included. All will be tested in the Copenhagen Psychophysiological Test-Battery (CPTB) following administration of papaverine (test day 1) and placebo (test day 2). The order of the test days will be randomized

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